Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting approximately four million individuals in the US and is the most common cause of dementia in North America and Europe. Genetic factors play an important role in the pathogenesis of AD. Heritability is estimated between 58 and 79% based on twin studies, including a large twin study from the Swedish Twin Registry. Our long term goal is to identify genetic variants that may serve as biomarkers for early diagnosis and/or may suggest novel targets for therapeutic intervention. Recently copy number variants (CNVs) have been recognized as important mechanisms of genetic variation contributing to disease phenotypes. In a cases-only genome-wide CNV association study looking for loci affecting AAO of AD we have identified a chromosomal segment on 14q11.2 (reference sequence position 19.3-19.5 Mb) where gene dosage is associated with AAO of AD (genome-wide adjusted p<0.032) We replicated the association in an independent cohort of 507 subjects using independent experimental and statistical methods. Interestingly, this region encompasses a cluster of olfactory receptors, shedding light onto the ongoing debate regarding a role of olfactory dysfunction in AD. Our specific hypothesis to be tested is that Olfactory Receptor-CNVs or patterns modify Age at Onset of AD. We propose to develop a custom aCGH covering all OR genes to comprehensively study the ORs. The array approach allows complete coverage of all of the OR regions in order to establish their modifier effect on AAO. This study will be an add-on to an ongoing multicenter prospective cohort study in the State of Texas (Texas Alzheimer Research Consortium, TARC). This aspect of the proposal will provide the preliminary data for future clinical studies for example addressing the predictive value of the modifiers in prospective cohorts of patients with MCI. 850 subjects (500 AD, 250 MCI and 100 normal controls) will be enrolled. Baseline and yearly longitudinal neuropsychological measures are being ascertained and entered into the TARC database. Subjects consented to genetic testing and DNA was extracted and banked. The protocol will be amended with the olfactory phenotyping. We will correlate the olfactory genotype and phenotype using the aCGH and the University of Pennsylvania Smell Identification Test (UPSIT) measure. We will compare cognitive profiles at presentation between the various OR copy number states to assess whether there is a cognitive endophenotype associated with the OR genotypes. The candidate is a physician scientist (board certified in Neurology) with the long-term goal of dedicating her scientific carrier to translational research in the field of AD. Her mentored research experience is with James R. Lupski, MD, PhD, one of the founders of the field of genomic disorders, who will continue his mentorship during this award and support the candidate to become an independent scientist. Chad Shaw, PhD statistician will be the co-mentor with extensive experience on array data analysis. Rachelle S. Doody, MD, PhD will be a co-mentor on the clinical research aspects of the project and on the clinical manifestations of AD. Dr. Jerry Schellenberg will mentor the candidate on Alzheimer genetics and guide with research directions, advice on manuscripts and grant applications. The candidate's clinical activity is focused on neurogenetics with interest in familial dementia. This creates the optimal setting for the proposed research. The short-term goals are to i) learn analyses techniques of large datasets in the era of technical acceleration which allows the generation of large numbers of genetic data points (array experiments), ii) further the knowledge in the clinical phenotype, and iii) comprehensively study the signal identified in the exploratory pilot study. These skills will provide an opportunity to become an independent scientist in the field of AD genomics, and to have the knowledge that is required to implement these discoveries into clinical practice irrespective of who will identify the CNV(s) that is/are associated with AD or one of its endophenotypes. We propose to identify genetic markers that modify disease onset of AD. If the age of disease onset can be delayed by 5 years the overall public health burden of AD will decrease by half by the year 2047. These specific genetic markers are attractive risk factor candidates because gene dosage can be modified by small molecules (medications) thus may translate to therapy that delays disease onset.